Nitrogenous tetrahydropyridyl-alkyl-heterocycles with TNF activity

ABSTRACT

This invention relates to nitrogenous (tetrahydropyridyl)(alkyl)heterocycles, to pharmaceutical compositions comprising them, to processes for preparing them and to the method of use thereof in the treatment of pain and diseases related to immune and inflammatory disorders.

The present invention relates to novel nitrogenous(tetrahydropyridyl)(alkyl)heterocycles, in particular nitrogenousmonocyclic heterocycles, to the pharmaceutical compositions comprisingthem and to a process for their preparation.

WO 98/25903 discloses 1-phenylalkyl-1,2,3,6-tetrahydropyridines for thetreatment of Alzheimer's disease.

WO 01/29026 discloses phenyl- and pyridyltetrahydropyridines having aninhibitory activity with regard to TNF-α (Tumor Necrosis Factor).

Bourrié et al. (Proc. Natl. Acad. Sci., 1999, 96(22), 12855–12859) havedescribed the activity of a compound known as SR 57746(1-(2-(naphth-2-yl)ethyl)-4-(3-trifluoromethyl)-1,2,3,6-tetrahydropyridine)in an experimental autoimmune encephalomyelitis (EAE) model and in themodulation of TNF-α.

TNF-α is a cytokine which has recently aroused interest as mediator ofimmunity, inflammation, cell proliferation, fibrosis, and the like. Thismediator is extensively present in inflamed synovial tissue and exertsan important role in the pathogenesis of autoimmunity (Annu. Rep. Med.Chem., 1997, 32, 241–250).

It has now been found that some tetrahydropyridines substituted bynitrogenous monocyclic heterocyclic derivatives have a powerful activitywith regard to modulating TNF-α.

Thus, the present invention relates, according to one of its aspects, to(tetrahydropyridyl)(alkyl)benzodiazines of formula (I):

in which

-   X represents N or CH;-   R₁ represents a hydrogen or halogen atom or a CF₃ group;-   R₂ and R₃ independently represent a hydrogen atom or a (C₁–C₄)alkyl    group;-   R₄ represents a hydrogen atom or a (C₁–C₄)alkyl group;-   n is 0 or 1;-   A represents a nitrogenous heterocycle of formula (a)–(d):

where R₅ and R₆ each independently represent a hydrogen atom or a(C₁–C₄)alkyl or (C₁–C₄)alkoxy group;

-   and their N-oxides and their salts or solvates.

In the present description, the term “(C₁–C₄)alkyl” denotes a monovalentradical of a saturated, straight- or branched-chain, C₁–C₄ hydrocarbonand the term “(C₁–C₄) alkoxy” denotes a monovalent radical of asaturated, straight- or branched-chain, C₁–C₄ hydrocarbon bonded via anoxygen atom.

In the present description, the term “halogen” denotes an atom chosenfrom chlorine, bromine, iodine and fluorine.

Preferred compounds of formula (I) are those where n is zero.

Other preferred compounds are those where R₂ and R₃ are hydrogen.

Other preferred compounds are those where R₁ is a CF₃ group.

Other preferred compounds are those where X is CH and R₁ is in the3-position of the benzene.

Other preferred compounds are those where X is CH and R₁ is a CF₃ group.

Other preferred compounds are those where X is N and the pyridine thusformed is substituted in the 2,6-positions.

Other preferred compounds are those where the phenyl ring is substitutedby the nitrogenous heterocycle A in the 3-position.

The nitrogenous heterocycles of formula (a)–(d) respectively represent apyridine, a pyrimidine, a pyrazine or a pyridazine. These heterocyclescan, according to the present invention, be attached to the remainder ofthe molecule of formula (I) via any one of the carbon atoms of theavailable positions.

According to the present invention, the compounds of formula (I) canexist as N-oxide derivatives. As indicated in the above formula, thecompounds of formula (I) can in particular carry the N-oxide group onthe tetrahyropyridine; alternatively, N-oxide groups may be present onthe nitrogens of the groups (a)–(d) and, optionally, all the nitrogensof the compounds of formula (I) can be simultaneously oxidized.

The salts of the compounds of formula (I) according to the presentinvention comprise both addition salts with pharmaceutically acceptableinorganic or organic acids, such as the hydrochloride, hydrobromide,sulfate, hydrogensulfate, dihydrogen-phosphate, citrate, maleate,tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate,and the like, and addition salts which make possible suitable separationor crystallization of the compounds of formula (I), such as the picrateor oxalate, or addition salts with optically active acids, for examplecamphorsulfonic acids and mandelic or substituted mandelic acids.

The optically pure stereoisomers and the mixtures of isomers of thecompounds of formula (I) due to the asymmetric carbon, when one of R₂and R₃ are different from one another, in any proportion, form part ofthe present invention.

The compounds of formula (I) can be prepared by a condensation reactionfrom a compound of formula (II):

in which X and R₁ are as defined above, with a compound of formula(III):

in which R₂, R₃, R₄, n and A are as defined above and L is a leavinggroup, isolation of the compound of formula (I) and optional conversionto one of its salts or solvates or to its N-oxide derivatives.

The condensation reaction is normally carried out by mixing the startingcompounds (II) and (III) in an inert organic solvent according toconventional methods.

The term “inert organic solvent” is understood to mean a solvent whichdoes interfere with the reaction. Such solvents are, for example,alcohols, such as methanol, ethanol, propan-2-ol or butanol.

It is possible, as leaving group L, for example, to use a halogen, suchas a chlorine or bromine atom, or else a methylsulfonyloxy group(CH₃—SO₂—O—).

The reaction is carried out at a temperature of between −10° C. and thereflux temperature of the reaction mixture, the reflux temperature beingpreferred.

The reaction can be suitably carried out in the presence of a protonacceptor, for example of an alkaline carbonate or of a tertiary amine,such as triethylamine.

The reaction is generally brought to a conclusion after a few hours;usually from 1 to 6 hours suffice to bring the condensation tocompletion.

The required compound is isolated according to conventional techniquesin the free base form or in the form of one of its salts. The free basecan be converted to one of its salts by simple salification in anorganic solvent, such as an alcohol, preferably ethanol or isopropanol,an ether, such as 1,2-dimethoxyethane, ethyl acetate, acetone or ahydrocarbon, such as hexane.

The compound of formula (I) obtained is isolated according toconventional techniques and is optionally converted to one of its saltsor solvates or to its N-oxide derivatives.

The starting compounds of formula (II) are known or else they can beprepared analogously to the known compounds.

The starting compounds of formula (III) are novel and constitute afurther subject matter of the present invention. These compounds can beprepared from the corresponding acids or esters by reduction of thecarboxyl group to an alcohol group and substitution of the OH by thedesired L group according to conventional methods. Alternatively, thesecompounds are prepared by Stille or Suzuki coupling of the two suitablysubstituted phenyl and heterocycle rings; according to these couplings,a suitable halophenyl is reacted with respectively trialkylstannane ordiborane derivatives of a heterocycle ring or, conversely, anappropriate haloheterocycle is reacted with respectivelytrialkylstannane or diborane derivatives of the phenyl ring. After thecoupling, the rings are optionally functionalized by conversion of thegroups present, according to well known methods. Examples of thepreparation of nitrogenous (trialkylstannane)heterocyclic compounds arereported in Bioorganic and Medicinal Chemistry, 9/2001, 2683–2691. Otherexamples of the above reactions are recorded in the experimental part.

Alternatively, the compounds of formula (I) can also be prepared by aprocess which plans:

-   (a) to react the compound of formula (VI):

-    in which X and R₁ are defined as above, with a functional    derivative of the acid of formula (VII)

-    in which R₂, R₃, R₄, n and A are as defined above,-   (b) to reduce the carbonyl group of the compound of formula (VIII)    thus obtained:

-   (c) to dehydrate the intermediate piperidinol of formula (IX) thus    obtained:

-   (d) to isolate the compound of formula (I) thus obtained and,    optionally, to convert it to one of its salts or solvates or to its    N-oxide derivatives.

The reaction of stage (a) can be suitably carried out in an organicsolvent at a temperature of between −10° C. and the reflux temperatureof the reaction mixture.

It may be preferable to carry out the reaction under cold conditionswhen it is exothermic, as in the case where the chloride is used asfunctional derivative of the acid of formula (VII).

The acids of formula (VII) above are novel and represent a furthersubject matter of the present invention. These compounds can be preparedfrom the products obtained by the Stille or Suzuki couplings mentionedabove, in particular by conversion of the substituents present on thephenyl to the desired acid groups.

Use may be made, as appropriate functional derivative of the acid offormula (VII), of the free acid, which is optionally activated (forexample with BOP=tri(dimethylamino)benzotriazol-1-yloxyphosphoniumhexafluorophosphate), an anhydride, a mixed anhydride, an active esteror an acid halide, preferably the bromide. Among the active esters, thep-nitrophenyl ester is particularly preferred but the methoxyphenyl,trityl, benzhydryl and similar esters are also suitable.

Use is preferably made, as reaction solvent, of a halogenated solvent,such as methylene chloride, dichloroethane, 1,1,1-trichloroethane,chloroform and the like, but also other organic solvents compatible withthe reactants employed, for example dioxane, tetrahydrofuran or ahydrocarbon, such as hexane, can likewise be employed.

The reaction can be suitably carried out in the presence of a protonacceptor, for example of an alkaline carbonate or of a tertiary amine,such as triethylamine.

The reduction of stage (b) can be suitably carried out with appropriatereducing agents, such as borane complexes, for example borane-dimethylsulfide ([CH₃]₂S—BH₃), aluminum hydrides or a complex hydride of lithiumand of aluminum, in an inert organic solvent at a temperature of between0° C. and the reflux temperature of the reaction mixture, according toconventional techniques.

The term “inert organic solvent” is understood to mean a solvent whichdoes not interfere with the reaction. Such solvents are, for example,ethers, such as diethyl ether, tetrahydrofuran (THF), dioxane or1,2-dimethoxyethane.

Alternatively, the compounds of formula (I) can also be prepared by acondensation/reduction reaction, starting from a compound of formula(II):

in which X and R₁ are as defined above, with an aldehyde of formula (X):

in which R₂, R₃, R₄, n and A are as defined above, isolation of thecompound of formula (I) and optional conversion to one of its salts orsolvates or to its N-oxide derivatives.

The condensation/reduction reaction is carried out by mixing thestarting compounds (II) and (X) in an organic solvent, such as analcohol, such as, for example, methanol, in an acidic medium, in thepresence of a reducing agent, such as sodium cyanoborohydride, accordingto conventional methods.

The compounds of formula (I) carrying an N-oxide group on the nitrogenatoms of the groups (a)–(d) can be prepared from the N-oxide derivativesof the compounds of formula (III) or (X).

The compounds of formula (I) carrying an N-oxide group on the nitrogenatom of the tetrahydropyridine or of the pyridine bonded to thetetrahydropyridine when X is N can be prepared by oxidation of thecorresponding compounds of formula (I). In this case, the compound offormula (I), such as obtained, for example, by the above synthesis, issubjected to an oxidation reaction according to conventional methods,for example to a reaction with m-chloroperbenzoic acid, in a suitablesolvent, and is isolated according to conventional techniques well knownto a person skilled in the art.

The compounds of the invention have properties which are advantageouswith respect to the inhibition of TNF-α.

These properties were demonstrated using a test aimed at measuring theeffect of molecules on TNF-α synthesis induced in Balb/c mice bylipopolysaccharide (LPS) of Escherichia coli (055:B5, Sigma, St Louis,Mo.).

The products to be tested are administered orally to groups of 5 femaleBalb/c mice (Charles River, France) aged from 7 to 8 weeks. One hourlater, the LPS is administered intravenously (10 μg/mouse). A bloodsample is taken from each animal 1.5 hours after administration of theLPS. The samples are centrifuged and the plasma is recovered and frozenat −80° C. The TNF-α is measured using commercial kits (R and D,Abingdon, UK).

In this test, compounds representative of the invention proved to bevery active, inhibiting TNF-α synthesis even at very low doses.

Due to this activity and to their low toxicity, the compounds of formula(I) and its salts or solvates can indeed be used in the treatment ofdiseases related to immune and inflammatory disorders or as analgesics.In particular, the compounds of formula (I) can be used to treatatherosclerosis, autoimmune diseases, diseases which lead to thedemyelinization of neurones (such as multiple sclerosis), asthma,rheumatoid arthritis, fibrotic diseases, idiopathic pulmonary fibrosis,cystic fibrosis, glumerulonephritis, rheumatoid spondylitis,osteoarthritis, gout, bone and cartilage resorption, osteoporosis,Paget's disease, multiple myeloma, uveoretinitis, septic shock,septicemia, endotoxic shock, graft-versus-host reaction, graftrejection, adult respiratory distress syndrome, silicosis, asbestosis,pulmonary sarcoidosis, Crohn's disease, ulcerative colitis, amyotrophiclateral sclerosis, Alzheimer's disease, Parkinson's disease, lupuserythematosus disseminatus, hemodynamic shock; ischemic pathologicalconditions (myocardial infarction, myocardial ischemia, coronaryvasospasm, angina pectoris, cardiac insufficiency, heart attack),postischemic reperfusion injuries, malaria, mycobacterial infections,meningitis, leprosy, viral infections (HIV, cytomegalovirus, herpesvirus), AIDS-related opportunistic infections, tuberculosis, psoriasis,atopic and contact dermatosis, diabetes, cachexia, cancer andradiation-mediated damage.

The compounds of formula (I) and their pharmaceutically acceptable saltsand solvates are preferably administered orally.

In the oral pharmaceutical compositions of the present invention, theactive principle can be administered in unit administration forms, as amixture with conventional pharmaceutical carriers, to animals and humanbeings for the treatment of the abovementioned conditions. Theappropriate unit administration forms comprise, for example, tablets,optionally scored, gelatin capsules, powders, granules and solutions orsuspensions to be taken orally.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle, such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose or other appropriatematerials or can be treated so that they have a prolonged or delayedactivity and so that they continuously release a predetermined amount ofactive principle.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and by pouring the mixture obtainedinto soft or hard gelatin capsules.

A preparation in the syrup or elixir form can comprise the activeingredient in conjunction with a sweetener, preferably a calorie-freesweetener, methylparaben and propylparaben as antiseptics, and anappropriate colorant and flavoring.

The water-dispersible powders or granules can comprise the activeingredient as a mixture with dispersing agents, wetting agents orsuspending agents, such as polyvinylpyrrolidone, and with sweeteners orflavor enhancers.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions according to the present invention,the active principle can also be in the form of an inclusion complex incyclodextrins, their ethers or their esters.

The amount of active principle to be administered depends, as always, onthe degree of progression of the disease and also on the age and weightof the patient. Nevertheless, the unit doses generally comprise from0.001 to 100 mg, better still from 0.01 to 50 mg, preferably from 0.1 to20 mg, of active principle, advantageously from 0.5 to 10 mg.

According to another of its aspects, the present invention relates to acombination comprising a compound of formula (I) or one of itspharmaceutically acceptable salts or solvates and at least one compoundchosen from immunosuppressants, such as interferon beta-1b;adrenocorticotropic hormone; glucocorticoids, such as prednisone ormethylprednisolone; or interleukin-1 inhibitors.

More particularly, the invention relates to a combination comprising acompound of formula (I) or one of its pharmaceutically acceptable saltsor solvates and at least one compound chosen from roquinimex(1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-3-quinoline-carboxanilide),myloran (product from Autoimmune comprising bovine myelin), antegren(monoclonal human antibody from Elan/Athena Neurosciences) orrecombinant interferon beta-1b.

Other possible combinations are those composed of a compound of formula(I) or one of its pharmaceutically acceptable salts or solvates and apotassium-channel blocker, such as, for example, fampridine(4-aminopyridine).

According to another of its aspects, the invention relates to a methodfor the treatment of diseases related to immune and inflammatorydisorders and in the treatment of pain, in particular atherosclerosis,autoimmune diseases, diseases which lead to the demyelinization ofneurones (such as multiple sclerosis), asthma, rheumatoid arthritis,fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis,glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, boneand cartilage resorption, osteoporosis, Paget's disease, multiplemyeloma, uveoretinitis, septic shock, septicemia, endotoxic shock,graft-versus-host reaction, graft rejection, adult respiratory distresssyndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn's disease,ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer's disease,Parkinson's disease, lupus erythematosus disseminatus, hemodynamicshock, ischemic pathological conditions (myocardial infarction,myocardial ischemia, coronary vasospasm, angina pectoris, cardiacinsufficiency, heart attack), postischemic reperfusion injuries,malaria, mycobacterial infections, meningitis, leprosy, viral infections(HIV, cytomegalovirus, herpes virus), AIDS-related opportunisticinfections, tuberculosis, psoriasis, atopic and contact dermatosis,diabetes, cachexia, cancer and radiation-mediated damage, comprising theadministration of a compound of formula (I) or of one of itspharmaceutically acceptable salts or solvates, alone or in combinationwith other active principles.

According to a subsequent aspect, the invention relates to a medicamentcomprising, as active principle, at least one compound of formula (I) orone of its pharmaceutically acceptable salts or solvates.

The following examples illustrate the invention.

PREPARATION 1 3-[4-(2-(Methylsulfonyloxy)ethyl)phenyl]pyridine (i)3-[4-(2-Hydroxyethyl)phenyl]pyridine

1 g (6.8 mmol) of (3-pyridyl)diethylborane, 0.87 ml (10.2 mmol) of2-(4-bromophenyl)ethanol, 1.53 g (27 mmol) of KOH powder, 1.1 g (3.4mmol) of tetrabutylammonium bromide and 0.39 g (0.34 mmol) oftetrakis(triphenylphosphine)Pd are mixed in 25 ml of anhydrous THF. Themixture is heated at reflux under a stream of argon for 4 hours. Themixture is poured into water, extraction is carried out with ethylacetate, the organic phase is dried and the solvent is evaporated. Theresidue is purified by chromatography on a column of silica gel, elutionbeing carried out with a cyclohexane/ethyl acetate=1/1 mixture, thetitle product thus being obtained.

(ii) 3-[4-(2-(Methylsulfonyloxy)ethyl)phenyl]pyridine

1 g (4.6 mmol) of the product from the preceding stage is dissolved in6.9 ml of methylene chloride and the solution is cooled to 0° C. 0.64 mlof triethylamine is added, followed, dropwise, by a solution of 0.36 ml(4.6 mmol) of methanesulfonyl chloride in 0.46 ml of methylene chloride.The mixture is stirred at 0° C. for 30 minutes and subsequently atambient temperature for 4 hours. The mixture is poured into water,extraction is carried out with ethyl acetate, the organic phase is driedand the solvent is evaporated. The residue is purified by chromatographyon a column of silica gel, elution being carried out with acyclohexane/ethyl acetate=2/8 mixture, the title product thus beingobtained.

M.p. 66–68° C.

PREPARATION 2 2-[4-(2-(Methylsulfonyloxy)ethyl)phenyl]pyridine (i)2-[4-(2-Hydroxyethyl)phenyl]pyridine

1 ml (10.5 mmol) of 2-bromopyridine in 80 ml of anhydrous THF is cooledto −78° C. under a stream of argon, 9.4 ml (15 mmol) of 1.6N n-BuLi inhexane are added thereto and the mixture is stirred for 30 minutes. 3.2ml (12 mmol) of tributyltin chloride are thus added and the mixture isstirred, still at −78° C., for 2 hours and afterwards at −20° C. for 3hours. It is poured into an aqueous NH₄Cl solution and extracted withethyl acetate. The organic phase is dried and the solvent is evaporated.The residue is purified by chromatography on a column of silica gel,elution being carried out with a cyclohexane/ethyl acetate=9/1 mixture,2.5 g of 2-(tributyltin)pyridine thus being obtained in the form of ayellow oil. 0.31 g of the product thus obtained is dissolved in 5 ml oftoluene, and 0.13 ml (0.92 mmol) of 2-(4-bromophenyl)ethanol and 49 mg(0.042 mmol) of tetrakis(triphenylphosphine)Pd are added thereto. Themixture is heated at reflux under a stream of argon for 6 hours. Themixture is poured into water, extraction is carried out with ethylacetate, the organic phase is dried and the solvent is evaporated. Theresidue is purified by chromatography on a column of silica gel, elutionbeing carried out with a cyclohexane/ethyl acetate=1/1 and subsequently4/6 mixture, the title product thus being obtained.

(ii) 2-[4-(2-(Methylsulfonyloxy)ethyl)phenyl]pyridine

By carrying out the reaction as described in Preparation 1(ii) but usingthe product from the preceding stage instead of the product fromPreparation 1(i), the title compound is obtained.

PREPARATION 3 (4-(4-Pyridyl)phenyl)acetic acid (i)4-(4-Pyridyl)acetophenone

0.85 g (5.6 mmol) of 4-bromopyridine, 1 g (6.1 mmol) of(4-acetylphenyl)boronic acid, 1.26 g (12 mmol) of sodium carbonate and260 mg of tetrakis(triphenylphosphine)Pd are mixed in 25 ml of THF and 6ml of water. The mixture is heated at 90° C. under a stream of nitrogenfor 2 hours. The mixture is poured into water, extraction is carried outwith diethyl ether, the organic phase is dried and the solvent isevaporated. The residue is purified by chromatography on a column ofsilica gel, elution being carried out with a cyclohexane/ethylacetate=3/7 mixture, the title product thus being obtained in the formof a white solid.

M.p. 88–90° C.

(ii) (4-(4-Pyridyl)phenyl)acetic acid

1.5 g (7.6 mmol) of the product from the preceding stage, 0.29 g ofsulfur, 3.6 ml of morpholine and a catalytic amount of p-toluenesulfonicacid monohydrate are mixed and the mixture is heated at 130° C. under astream of nitrogen. After 6 hours, the mixture is cooled, 7 ml ofabsolute ethanol are added and the mixture is stirred at ambienttemperature overnight. 1.5 g of thioamide thus formed are dissolved in asolution of 12.3 ml of ethanol, 56.2 ml of water and 0.6 g of NaOH, andthe solution is heated at reflux for 3 hours. It is subsequentlyacidified with a dilute hydrochloric acid solution and the solvents areevaporated. The title compound is thus obtained.

PREPARATION 4 (4-(6-Methylpyrid-3-yl)phenyl)acetic acid (i)4-(6-Methylpyrid-3-yl)acetophenone

0.25 g (1.1 mol) of 3-trifluoromethylsulfonate-6-methylpyridine, 0.18 g(1 mmol) of (4-acetylphenyl)boronic acid, 1.3 ml of a 2M sodiumcarbonate solution, 38 mg of tetrakis(triphenylphosphine)Pd and 85 mg (2mmol) of LiCl are mixed in 9 ml of anhydrous 1,2-dimethoxyethane. Themixture is heated at 75° C. for 3 hours. The mixture is poured intowater, extraction is carried out with diethyl ether, the organic phaseis dried and the solvent is evaporated. The residue is treated in hexaneand the title product is thus obtained in the form of a white solid.

M.p. 94–96° C.

(ii) (4-(6-Methylpyrid-3-yl)phenyl)acetic acid

By carrying out the reaction as described in Preparation 3(ii) but usingthe product from the preceding stage instead of the product fromPreparation 3(i), the title compound is obtained.

PREPARATION 5 3-[3-(2-Bromoethyl)phenyl]pyridine Hydrobromide (i)3-[3-(2-Hydroxyethyl)phenyl]pyridine

By carrying out the reaction as described in Preparation 1 but using2-(3-bromophenyl)ethanol instead of 2-(4-bromophenyl)ethanol, the titlecompound is obtained.

(ii) 3-[3-(2-Bromoethyl)phenyl]pyridine Hydrobromide

The product from the preceding stage is dissolved in 6 ml of 48%hydrobromic acid and the solution is heated at 125° C. for 6 hours.Dilution is carried out with 2 ml of water and the precipitated productis filtered off. The title product is thus obtained.

PREPARATION 6 (4-(5-Pyrimidinyl)phenyl)acetic acid (i)4-(5-Pyrimidinyl)acetophenone

By carrying out the reaction as described in Preparation 4 but using5-bromopyrimidine instead of3-trifluoromethanesulfonate-6-methylpyridine, the title compound isobtained.

M.p. 134–136° C.

(ii) (4-(5-Pyrimidinyl)phenyl)acetic acid

By carrying out the reaction as described in Preparation 3(ii) but usingthe product from the preceding stage instead of the product fromPreparation 3(i), the title compound is obtained.

PREPARATION 7 4-[3-(2-Bromoethyl)phenyl]pyridine

By carrying out the reaction as described in Preparation 5 but using4-(4,4,5,5-tetramethyl[1,3,2]dioxaboran-2-yl)pyridine instead of(3-pyridyl)diethylborane, the title compound is obtained in the form ofa yellow oil.

PREPARATION 8 2-[3-(2-Chloroethyl)phenyl]pyridine (i)2-[3-(2-Hydroxyethyl)phenyl]pyridine

By carrying out the reaction as described in Preparation 2(i) but using2-(3-bromophenyl)ethanol instead of 2-(4-bromophenyl)ethanol, the titlecompound is obtained in the form of a yellow oil.

(ii) 2-[3-(2-Chloroethyl)phenyl]pyridine

The product from the preceding stage in 17 ml of dichloromethane iscooled to 0° C. and 11 ml of SOCl₂ are added thereto. The mixture isstirred overnight at ambient temperature and is poured into a water/icemixture, the pH is brought to neutrality by addition of sodiumbicarbonate, extraction is carried out with dichloromethane, the organicphase is dried and the solvent is evaporated. The title compound isobtained in the form of a yellow oil.

PREPARATION 9 4-[3-(2-Chloroethyl)phenyl]pyridine (i)4-[3-(2-Hydroxyethyl)phenyl]pyridine

By carrying out the reaction as described in Preparation 5(i) but using4-(4,4,5,5-tetramethyl [1,3,2]dioxaboran-2-yl)pyridine instead of(3-pyridyl)diethylborane, the title compound is obtained in the form ofa yellow oil.

(ii) 4-[3-(2-Chloroethyl)phenyl]pyridine

By carrying out the reaction as described in Preparation 8(ii) but usingthe product from the preceding stage, the title compound is obtained inthe form of a yellow oil.

PREPARATION 10 3-[3-(2-Chloroethyl)-4-methylphenyl]pyridine (i)4-[3-(2-Hydroxyethyl)-4-methylphenyl]pyridine

By carrying out the reaction as described in Preparation 1(i) but using2-(3-bromo-4-methylphenyl)ethanol instead of 2-(4-bromophenyl)ethanol,the title compound is obtained.

(ii) 4-[3-(2-Chloroethyl)-4-methylphenyl]pyridine

By carrying out the reaction as described in Preparation 8(ii) but usingthe product from the preceding stage, the title compound is obtained.

PREPARATION 11 3-(4-Pyridyl 1-oxide)phenylacetaldehyde

2.5 g (0.015 mol) of 4-(3-hydroxyphenyl)pyridine and 40 ml of pyridineand 2.3 g of 4-(dimethylamino)pyridine (DMAP) are cooled to 0° C. 3.2 mlof triflic anhydride are added thereto dropwise. The mixture is stirredat 0° C. for one hour and at ambient temperature overnight. It is pouredinto a water/ice mixture, extraction is carried out with ethyl acetate,the organic phase is dried and the solvent is evaporated under reducedpressure. The crude product is purified by chromatography on a column ofsilica gel, elution being carried out with a cyclohexane/ethylacetate=8/2 mixture. 4-(3-Hydroxyphenyl)pyridinetrifluoromethanesulfonate is obtained in the form of an oil. 2.26 g ofthis product are mixed with 112 ml of anhydrous dimethylformamide, 38 gof palladium acetate, 2.5 ml of anhydrous triethylamine and 2 g ofN,N-dimethylethanolamine vinyl ether. The mixture is heated at 80° C.for 48 hours. The solvent is evaporated under reduced pressure. Theresidue is purified by flash chromatography on a column of silica gel,elution being carried out with ethyl acetate, to remove the firstproduct, and subsequently with an ethyl acetate/methanol=1/1 mixture.2-[2-[3-(4-Pyridyl)-phenyl)ethenyl)oxy)]-N,N-dimethyl-1-ethanamine isobtained. 0.53 g of this product, dissolved in 35 ml of methanol, istreated with 20 ml of water and 5 ml of 96% sulfuric acid. The mixtureis heated at 60° C. for 6 hours and is poured into ice, a saturatedaqueous NaHCO₃ solution is added thereto and extraction is carried outwith ethyl acetate. The organic phase is dried and the solvent isevaporated under reduced pressure. 3-(4-Pyridyl)phenylacetaldehydedimethyl acetal is obtained. Its N-oxide derivative is prepared byreaction with m-chloroperbenzoic acid in methylene chloride and thealdehyde is subsequently released by reaction with a mixture oftrifluoroacetic acid, water and methylene chloride. The title compoundis thus obtained.

EXAMPLE 11-[2-(4-(3-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its dihydrochloride

0.85 g (2.9 mmol) of the product from Preparation 1 is dissolved in 14ml of isopropanol, and 1.21 ml of triethylamine and 700 mg (2.9 mmol) of4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine are addedthereto. The mixture is heated at reflux for 4 hours, is poured intowater and is extracted with ethyl acetate. The organic phase is dried,the solvent is evaporated under reduced pressure and the crude prdouctis obtained, which product is purified by chromatography on a column ofsilica gel, elution being carried out with ethyl acetate. The titleproduct is thus obtained. Its dihydrochloride salt is prepared byreaction with of the acid of a solution of isopropanol saturated withhydrochloric acid.

M.p. 235–257° C. (dihydrochloride)

EXAMPLE 21-[2-(4-(2-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its dihydrochloride

By carrying out the reaction as described in Example 1 but using theproduct from Preparation 2, the title compound is obtained. Thehydrochloride is prepared using a solution of isopropanol saturated withhydrochloric acid.

M.p. 253–256° C. (hydrochloride)

EXAMPLE 31-[2-(4-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its dihydrochloride

2.4 g of the product from Preparation 3 are dissolved in 20 ml ofmethylene chloride, 1.23 g (5 mmol) of4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidine, 2.2 g (5 mmol) of BOPand 2.1 ml of triethylamine are added thereto and the mixture is stirredat ambient temperature overnight. A mixture of ethyl acetate and ofwater is added, the two phases are separated, the organic phase is driedover sodium sulfate and the solvent is evaporated. The crude product ispurified by chromatography on a column of silica gel, elution beingcarried out with an ethyl acetate/methanol=9/1 mixture. 1.1 g of theproduct thus obtained, dissolved in 32 ml of anhydrous THF, are pouredinto a suspension of 0.19 g (5 mmol) of LiAlH₄ in 4.5 ml of anhydrousTHF at 0° C. under a stream of nitrogen. The mixture is stirred atambient temperature for 5 hours, is poured into a water/ice mixture andis extracted with ethyl acetate. The two phases are separated, theorganic phase is dried over sodium sulfate and the solvent isevaporated. 0.65 g of the product, thus reduced, is dissolved in 3.9 mlof acetic acid, 0.78 ml of 96% sulfuric acid is added thereto and themixture is heated at 80° C. for 2 hours. It is poured into an NaOH/icemixture and is extracted with ethyl acetate. The organic phase is washedwith water, is dried and is evaporated under reduced pressure. The crudeproduct is purified by chromatography on a column of silica gel, elutionbeing carried out with an ethyl acetate/methanol=95/5 mixture. The titlecompound is thus obtained. The dihydrochloride salt is prepared using asolution of isopropanol saturated with hydrochloric acid.

M.p. 179–181° C. (dihydrochloride)

EXAMPLE 41-[2-(4-(6-Methylpyrid-3-yl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its dihydrochloride

By carrying out the reaction as described in Example 3 but using theproduct from Preparation 4, the title compound is obtained.

M.p. 174–175° C. (dihydrochloride)

EXAMPLE 51-[2-(3-(3-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its dioxalate

By carrying out the reaction as described in Example 1 but using theproduct from Preparation 5 (free base), butanol instead of propan-2-oland potassium carbonate instead of triethylamine, the title compound isobtained. Its oxalate salt is prepared by treatment of the base withoxalic acid in acetone.

M.p. 152–157° C. (dioxalate)

EXAMPLE 61-[2-(4-(5-Pyrimidinyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

By carrying out the reaction as described in Example 3 but using theproduct from Preparation 6, the title compound is obtained.

M.p. 196–198° C. (hydrochloride)

EXAMPLE 71-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridineand its dioxalate Salt

By carrying out the reaction as described in Example 1 but using theproduct from Preparation 7, the title compound is obtained in the formof an oil. Its oxalate salt is prepared by treatment of the base withoxalic acid in acetone.

M.p. 140–144° C. (dioxalate)

EXAMPLES 8 TO 16

By following the reaction scheme of Example 1 but using appropriatestarting materials, the compounds listed in the table below areobtained:

Ex. 8⁽¹⁾

Oxalate saltM.p. 182–186° C. Ex. 9⁽¹⁾

Oxalate saltM.p. 126–129° C. Ex. 10⁽¹⁾

Oxalate saltM.p. 175–177° C. Ex. 11⁽²⁾

Oxalate saltM.p. 183–186° C. Ex. 12⁽³⁾

Oxalate saltM.p. 205–207° C. Ex. 13⁽³⁾

Oxalate saltM.p. 170–173° C. Ex. 14⁽³⁾

Oxalate saltM.p. 199–201° C. Ex. 15⁽³⁾

Mass: M⁺ 409TLC: R.f. 0.35(AcEt/MeOH = 8/2) Ex. 16⁽⁴⁾

TLC: R.f. 0.6(AcEt)Notes:

The starting materials are described in the above Preparations or elsethey can be prepared analogously to the latter; in particular:

-   (1) intermediate described in Preparation 8-   (2) intermediate described in Preparation 9-   (3) intermediates obtained by reaction of    [3-(2-hydroxyethyl)phenyl]boronic acid with appropriate    haloheterocycles-   (4) intermediate described in Preparation 10

The reaction solvent is preferably 4-methyl-2-pentanone (instead of theisopropanol described in Example 1)

-   TLC=thin layer chromatography-   AcEt=ethyl acetate-   MeOH=methanol

EXAMPLE 171-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine1-oxide

The N-oxide derivative of the compound of Example 7 is prepared byreaction with m-chloroperbenzoic acid in methylene chloride.

Thin layer chromatography (TLC): R.f. 0.15, eluent methanol.

EXAMPLE 18 1-[2-(3-(4-Pyridyl1-oxide)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine

0.24 g (0.001 mol) of4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine, 12 ml ofmethanol, 0.26 ml of glacial acetic acid and 0.12 g of sodium acetateare mixed. The mixture is cooled to 0–5° C. and 8 ml of methanol, 0.37 gof 3-(4-pyridyl 1-oxide)phenylacetaldehyde (as obtained by Preparation11) and, with care, 0.2 g of sodium cyanoborohydride are added thereto.The mixture is stirred at 0–5° C. for 0.5 hour and subsequently atambient temperature overnight. 3 ml of concentrated hydrochloric acidare added, the mixture is stirred for 15 minutes, the solvent isevaporated under reduced pressure and the residue is taken up in anethyl acetate/NH₄OH mixture. The organic phase is dried over sodiumsulfate and filtered, and the solvent is evaporated. The residue ispurified by chromatography on a column of silica gel, elution beingcarried out with an ethyl acetate/methanol=8/2 mixture. The titlecompound is obtained.

M.p. 142–145° C.

1. A compound of formula (1):

in which X is N or CH; R₁ is a hydrogen or halogen atom or a CF₃group;R₂ and R₃ independently are a hydrogen atom or a (C₁–C₄)alkyl group; R₄is a hydrogen atom or a (C₁–C₄)alkyl group; n is 0 or 1; and A is anitrogenous hetereocycle of formula (a)–(d):

where R₅ and R₆ each independtly are a hydrogen atom or a (C₁–C₄)alkylor (C₁–C₄)alkoxy group; or an N-oxide, salt or solvate ihereof.
 2. Thecompound as claimed in claim 1, where n is zero.
 3. The compound asclaimed in claim 1, where R₂ and R₃ are each hydrogen.
 4. The compoundas claimed in claim 1, where R₁ is a CF₃ group.
 5. The compound asclaimed in claim 1, where X is CH and R₁ is in the 3-position of thebenzene.
 6. The compound as claimed in claim 1, where X is N and thepyridine thus formed is substituted in the 2,6-positions.
 7. Thecompound as claimed in claim 1, where the phenyl ring is substituted bythe notrogenous heterocycle A in the 3-position.
 8. The compound asclaimed in claim 1 in the form of an N-oxide thereof.
 9. A compoundselected from the group consisting of:1-[2-(4-(3-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(4-(2-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(4-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(4-(6-Methylpyrid-3-yl)phenyl)ethyl]-4-(3-(triflouronmethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(3-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(4-(5-Pyrimidinyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(2-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(2-Pyridyl)phenyl)ethyl]-4-(6-(trifluoromethyl)pyrid-2-yl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(2-Pyridyl)phenyl)ethyl]-4-(3-flourophenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(2-Pyrazinyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(6-Methyl-3-pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(2-Pyrimidiyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(3-Pyridaziyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(3-Pyridyl)-4-methylphenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;1-[2-(3-(4-Pyridyl)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine1-oxide; and 1-[2-(3-(4-Pyridyl1-oxide)phenyl)ethyl]-4-(3-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine;or salt or solvent thereof.
 10. A process for the preparation of thecompound of formula (I) comprising reacting a compound of formula (II)

in which X and R₁ are as defined in claim 1, with a compound of formala(III):

in which R₂, R₃, R₄, n and A are as defined in claim 1 and L is aleaving group, isolating the compound of formula (I), and optionallyconverting the compound of formula (I) to a salt, solvate or N-oxidethereof.
 11. A pharmaceutical composition, comprising the comnound offormula (I) as claimed in claim 1 or a solvate or pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. 12.The composition as claimed in claim 11 comprising 0.001 to 100 mg of thecompound of formula (I).
 13. A method for the treatment of paincomprising administering to a patient in need of such treatment aneffective amount of the compound according to claim 1 or salt or solvatethereof.
 14. The compound as claimed in claim 2 in the form of anN-oxide thereof.
 15. The compound as claimed in claim 3 in the form ofan N-oxide thereof.
 16. The compound as claimed in claim 4 in the formof an N-oxide thereof.
 17. The compound as claimed in claim 5 in theform of an N-oxide thereof.
 18. The compound as claimed in claim 6 inthe form of an N-oxide thereof.
 19. The compound as claimed in claim 7in the form of an N-oxide thereof.
 20. A pharmaceutical composition,comprising the compound of formula (I) as claimed in claim 2 or solvateor pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 21. A pharmaceutical composition, comprising thecompound or formula (I) as claimed in claim 3 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 4 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 23. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 5 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 24. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 6 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 25. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 7 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 26. A pharmaceutical composititon, comprising thecompound of formula (I) as claimed in claim 8 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 27. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 9 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 28. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 14 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 29. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 15 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 30. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 16 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 31. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 17 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 32. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 18 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 33. A pharmaceutical composition, comprising thecompound of formula (I) as claimed in claim 19 or solvate orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 34. A method for the treatment of pain comprisingadministering to a patient in need of such treatment an effective amountof the compound according to claim 2 or salt or solvate thereof.
 35. Amethod for the treatment of pain comprising administering to a patientin need of such treatment an effective amount of the compound accordingto claim 3 or salt or solvate thereof.
 36. A method for the treatment ofpain comprising administering to a patient in need of such treatment aneffective amount of the compound according to claim 4 or salt or solvatethereof.
 37. A method for the treatment of pain comprising administeringto a patient in need of such treatment an effective amount of thecompound according to claim 5 or salt or solvate thereof.
 38. A methodfor the treatment of pain comprising administering to a patient in needof such treatment an effective amount of the compound according to claim6 or salt or solvate thereof.
 39. A method for the treatment of paincomprising administering to a patient in need of such treatment aneffective amount of the compound according to claim 7 or salt or solvatethereof.
 40. A method for the treatment of pain comprising administeringto a patient in need of such treatment an effective amount of thecompound according to claim 8 or salt or solvate thereof.
 41. A methodfor the treatment of pain comprising administering to a patient in needof such treatment an effective amount of the compound according to claim9 or salt or solvate thereof.
 42. A method for the treatment of paincomprising administering to a patient in need of such treatment aneffective amount of the compound according to claim 14 or salt orsolvate thereof.
 43. A method for the treatment of pain comprisingadministering to a patient in need of such treatment an effective amountof the compound according to claim 15 or salt or solvate thereof.
 44. Amethod for the treatment of pain comprising administering to a patientin need of such treatment an effective amount of the compound accordingto claim 16 or salt or solvate thereof.
 45. A method for the treatmentof pain comprising administering to a patient in need of such treatmentan effective amount of the compound according to claim 17 or salt orsolvate thereof.
 46. A method for the treatment of pain comprisingadministering to a patient in need of such treatment an effective amountof the compound according to claim 18 or salt or solvate thereof.
 47. Amethod for the treatment of pain comprising administering to a patientin need of such treatment an effective amount of the compound accordingto claim 19 or salt or solvate thereof.